Acute and chronic bone marrow toxicities are the major limiting factors in the treatment of cancer. They are both related to two causes. The first is a decrease in the number of hemopoietic cells (e.g., pluripotent stem cells and other progenitor cells) caused by both a lethal effect of cytotoxic agents or radiation on these cells and by differentiation of stem cells provoked by a feed-back mechanism induced by the depletion of more mature marrow compartments. The second cause is a reduction in self-renewal capacity of stem cells, which is also related to both direct (mutation) and indirect (aging of stem cell population) effects. Stimulators and inhibitors of bone marrow kinetics play a prominent role in the induction of damage and recovery patterns (Tubiana, M., et al., Radiotherapy and Oncology 29:1, 1993).
Acute myelosuppression as a consequence of cytotoxic chemotherapy is well recognized as a dose-limiting factor in cancer treatment. Although other normal tissues may be adversely affected, bone marrow is particularly sensitive to the proliferation-specific treatment such as chemotherapy or radiotherapy.
Self-renewing, pluripotent hemopoietic stem cells, as measured by spleen colony-forming units (CFU-S), are responsible for generation of the hemopoietic system (Till, J. E., et al., Radiat. Res. 14:213, 1961). Such stem cells are mainly quiescent, and renewal of mature cells is provided by the partially differentiated, lineage-committed hemopoietic progenitors. At this stage, the stem cells are relatively invulnerable to chemotherapy and radiotherapy that affects only those cells that are already in proliferation or about to begin proliferation. The stem cell compartment of the bone marrow that guarantees a sufficient supply of cells bound for differentiation, though mainly quiescent, still has approximately 10% of its cellular component in some state of mitosis (Lajtha, L. G., In Stem Cells, Ed: C. S. Potten, Churchill Livingstone, Edinburgh, 1-11, 1983). During chemotherapy or radiotherapy, the first treatment kills proliferating malignant or infected cells as well as proliferating hemopoietic cells in the bone marrow, but has no effect on the quiescent CFU-S. Therefore, the given situation before treatment is favorable for therapy as the stem cell population is relatively resistant. Subsequent treatment, however, will cause severe damage to the stem cell population, since they will have begun compensatory proliferation.